Myotonic Dystrophy type 1 (DM1) is a multisystemic, neuro-muscular disease without cure. DM1 pathologyis mainly mediated by untranslated RNA CUG repeats which misregulate two families of RNA CUG-bindingproteins, CUGBP1 and MBNL. In DM1, CUG repeats increase protein levels of CUGBP1. Consistent withthe elevation of CUGBP1 in DM1 patients, the overexpression of CUGBP1 in mice causes musculardystrophy, myotonia and a delay of skeletal muscle development and differentiation. It has been recentlyfound that the silencing of CUG repeats in mouse DM1 model reverses myotonia and muscular dystrophythrough normalization of CUGBP1. Despite this progress, mechanisms by which CUG repeats alter activitiesof CUGBP1 in DM1 cells are not well understood. We found that RNA binding activities of CUGBP1 andinteractions of CUGBP1 with initiation translation factor 2, eIF2, are regulated by Akt and cyclinD3/cdk4signal-transduction pathways. Akt controls cytoplasm/nucleus distribution of CUGBP1. CyclinD3/cdk4increases interactions of CUGBP1 with eIF2. In DM1 muscle, these signal transduction pathways aremisregulated. Cyclin D3 levels are reduced in DM1 myogenic cells, while Akt is up-regulated. Thesealterations change expression of CUGBP1 targets. Cdk4-mediated phosphorylation of CUGBP1 seems tobe critical for the prevention of interaction of CUGBP1 with expanded CUG repeats since the mutant S302Gmolecule binds significantly stronger to RNA CUG expansion. In addition, recent data showed that CUGrepeats also increase PKC-dependent phosphorylation of CUGBP1 leading to the stabilization of CUGBP1.Thus, the main hypothesis of this application is that in DM1 cells CUGn-mediated alterations of Akt,cyclinD3/cdk4, and PKC signal transduction pathways lead to (1) increase of CUGBP1 levels; (2) adelay of muscle differentiation; (3) increase of protein levels of a new CUGBP1 target, histonedeacetylase 1 (HDAC1), which will inhibit transcription of certain genes in DM1. In this application, wewill test the role of these upstream signal transduction pathways in the regulation of CUGBP1 stability, in theregulation of intracellular localization of CUGBP1 and in the epigenetic control of gene expression in DM1.We will examine the role of cyclin D3-cdk4 pathway in the delay of muscle differentiation by generation andexamination of CUGBP1-S302G knockin mice. The role of Akt-CUGBP1 pathway in the increasedproliferative rate of DM1 muscle will be examined in DM1 cultured cells and in CUGBP1-S28A knockin mice.Results of this study will help to develop approaches to normalize CUGBP1 activity in DM1 and to correctskeletal muscle differentiation in DM1 patients.

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Myotonic Dystrophy type 1 (DM1) is a multisystem; neuro-muscular disease which is caused by expansion ofun-translated CTG repeats increasing protein levels of CUG-binding protein; CUGBP1. My applicationproposes the elucidation of molecular mechanisms mis-regulating CUGBP1 activity in DM1 muscle. Results ofthis study will help to develop therapy to normalize CUGBP1 activity in DM1 patients.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Nuckolls, Glen H
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Cincinnati Children's Hospital Medical Center
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